Mutations in ap1b1 Cause Mistargeting of the Na(+)/K(+)-ATPase Pump in Sensory Hair Cells.

The hair cells of the inner ear are polarized epithelial cells with a specialized structure at the apical surface, the mechanosensitive hair bundle. Mechanotransduction occurs within the hair bundle, whereas synaptic transmission takes place at the basolateral membrane. The molecular basis of the development and maintenance of the apical and basal compartments in sensory hair cells is poorly understood. Here we describe auditory/vestibular mutants isolated from forward genetic screens in zebrafish with lesions in the adaptor protein 1 beta subunit 1 (ap1b1) gene. Ap1b1 is a subunit of the adaptor complex AP-1, which has been implicated in the targeting of basolateral membrane proteins. In ap1b1 mutants we observed that although the overall development of the inner ear and lateral-line organ appeared normal, the sensory epithelium showed progressive signs of degeneration. Mechanically-evoked calcium transients were reduced in mutant hair cells, indicating that mechanotransduction was also compromised. To gain insight into the cellular and molecular defects in ap1b1 mutants, we examined the localization of basolateral membrane proteins in hair cells. We observed that the Na(+)/K(+)-ATPase pump (NKA) was less abundant in the basolateral membrane and was mislocalized to apical bundles in ap1b1 mutant hair cells. Accordingly, intracellular Na(+) levels were increased in ap1b1 mutant hair cells. Our results suggest that Ap1b1 is essential for maintaining integrity and ion homeostasis in hair cells

Participatory Archival Research and Development: The Born-Digital Access Initiative

In an effort to advance the professional discourse around establishing best practices for access to born-digital archival collections, we designed a multi-phase, mixed-methods initiative, begun in 2014, that aimed to identify gaps and challenges in existing access methods and identify plans for how cultural heritage organizations hoped to improve access practices in the future. Over the course of our collaboration, our goals quickly evolved beyond the scope of collecting and publishing a static data set. We were inspired by models of research in practice, participatory action research, and research and development to translate our results into action by using the data to kickstart collaborative progress towards the future of archival practice. Through this paper, we synthesized our personal experiences of conducting the study, our exploration of existing models, and our aims and hopes for the future of research in our field into a framework for research in practice called Participatory Archival Research and Development (PAR&D)

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

Hair cells sense and transmit auditory, vestibular, and hydrodynamic information by converting mechanical stimuli into electrical signals. This process of mechano-electrical transduction (MET) requires a mechanically gated channel localized in the apical stereocilia of hair cells. In mice, lipoma HMGIC fusion partner-like 5 (LHFPL5) acts as an auxiliary subunit of the MET channel whose primary role is to correctly localize PCDH15 and TMC1 to the mechanotransduction complex. Zebrafish have two lhfpl5 genes (lhfpl5a and lhfpl5b), but their individual contributions to MET channel assembly and function have not been analyzed. Here we show that the zebrafish lhfpl5 genes are expressed in discrete populations of hair cells: lhfpl5a expression is restricted to auditory and vestibular hair cells in the inner ear, while lhfpl5b expression is specific to hair cells of the lateral line organ. Consequently, lhfpl5a mutants exhibit defects in auditory and vestibular function, while disruption of lhfpl5b affects hair cells only in the lateral line neuromasts. In contrast to previous reports in mice, localization of Tmc1 does not depend upon Lhfpl5 function in either the inner ear or lateral line organ. In both lhfpl5a and lhfpl5b mutants, GFP-tagged Tmc1 and Tmc2b proteins still localize to the stereocilia of hair cells. Using a stably integrated GFP-Lhfpl5a transgene, we show that the tip link cadherins Pcdh15a and Cdh23, along with the Myo7aa motor protein, are required for correct Lhfpl5a localization at the tips of stereocilia. Our work corroborates the evolutionarily conserved co-dependence between Lhfpl5 and Pcdh15, but also reveals novel requirements for Cdh23 and Myo7aa to correctly localize Lhfpl5a. In addition, our data suggest that targeting of Tmc1 and Tmc2b proteins to stereocilia in zebrafish hair cells occurs independently of Lhfpl5 proteins

Abstract

AimsPatients with spinal cord injury (SCI) are at risk of developing renal calculi. This study describes the management of renal calculi among patients with SCI with attention to factors influencing surgical management vs observation.MethodsThis retrospective, cohort study identified patients with SCI and renal calculi between 2009 to 2016 from an institutional neurogenic bladder database and detailed the management of their stones. A stone episode was defined as radiographic evidence of new calculi.ResultsOf 205 patients with SCI, 34 had renal stones, for a prevalence of 17%. The mean age was 50 years (range 22,77) and most had cervical SCI (n = 22, 65%). There were 41 stone episodes with 98 individual stones identified with a mean stone size of 4.9 mm (range 1‐19).Of the 41 episodes, 10 (24%) underwent surgery after initial diagnosis. Pain was the most common primary indication for surgery (n = 9, 60%). The median time from diagnosis to intervention for all patients was 4 months (interquartile range 1,23). Of the 41 episodes, 31 (76%) were initially observed and among these, 5 ultimately required surgery (16%) while 26 (84%) did not. Of these 26, 12 (46%) stones passed spontaneously and 14 (53%) remained unchanged. The need for surgery correlated with more stone episodes (P = .049).ConclusionIn this cohort of patients with SCI and small, nonobstructing renal stones, 76% (n = 31) were offered observation. Of these observed patients, 84% (n = 26) did not require further intervention at a median of 4 years of follow‐up.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151315/1/nau24091.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151315/2/nau24091_am.pd

Reward-Sensitive Basal Ganglia Stabilize the Maintenance of Goal-Relevant Neural Patterns in Adolescents

Maturation of basal ganglia (BG) and frontoparietal circuitry parallels developmental gains in working memory (WM). Neurobiological models posit that adult WM performance is enhanced by communication between reward-sensitive BG and frontoparietal regions, via increased stability in the maintenance of goal-relevant neural patterns. It is not known whether this reward-driven pattern stability mechanism may have a role in WM development. In 34 young adolescents (12.16–14.72 years old) undergoing fMRI, reward-sensitive BG regions were localized using an incentive processing task. WM-sensitive regions were localized using a delayed-response WM task. Functional connectivity analyses were used to examine the stability of goal-relevant functional connectivity patterns during WM delay periods between and within reward-sensitive BG and WM-sensitive frontoparietal regions. Analyses revealed that more stable goal-relevant connectivity patterns between reward-sensitive BG and WM-sensitive frontoparietal regions were associated with both greater adolescent age and WM ability. Computational lesion models also revealed that functional connections to WM-sensitive frontoparietal regions from reward-sensitive BG uniquely increased the stability of goal-relevant functional connectivity patterns within frontoparietal regions. Findings suggested (1) the extent to which goal-relevant communication patterns within reward-frontoparietal circuitry are maintained increases with adolescent development and WM ability and (2) communication from reward-sensitive BG to frontoparietal regions enhances the maintenance of goal-relevant neural patterns in adolescents’ WM. The maturation of reward-driven stability of goal-relevant neural patterns may provide a putative mechanism for understanding the developmental enhancement of WM

Detecting species-site dependencies in large multiple sequence alignments

Multiple sequence alignments (MSAs) are one of the most important sources of information in sequence analysis. Many methods have been proposed to detect, extract and visualize their most significant properties. To the same extent that site-specific methods like sequence logos successfully visualize site conservations and sequence-based methods like clustering approaches detect relationships between sequences, both types of methods fail at revealing informational elements of MSAs at the level of sequence–site interactions, i.e. finding clusters of sequences and sites responsible for their clustering, which together account for a high fraction of the overall information of the MSA. To fill this gap, we present here a method that combines the Fisher score-based embedding of sequences from a profile hidden Markov model (pHMM) with correspondence analysis. This method is capable of detecting and visualizing group-specific or conflicting signals in an MSA and allows for a detailed explorative investigation of alignments of any size tractable by pHMMs. Applications of our methods are exemplified on an alignment of the Neisseria surface antigen LP2086, where it is used to detect sites of recombinatory horizontal gene transfer and on the vitamin K epoxide reductase family to distinguish between evolutionary and functional signals

The influence of residential and workday population mobility on exposure to air pollution in the UK

Traditional approaches of quantifying population-level exposure to air pollution assume that concentrations of air pollutants at the residential address of the study population are representative for overall exposure. This introduces potential bias in the quantification of human health effects. Our study combines new UK Census data comprising information on workday population densities, with high spatio-temporal resolution air pollution concentration fields from the WRF-EMEP4UK atmospheric chemistry transport model, to derive more realistic estimates of population exposure to NO2, PM2.5 and O3. We explicitly allocated workday exposures for weekdays between 8:00 am and 6:00 pm. Our analyses covered all of the UK at 1 km spatial resolution. Taking workday location into account had the most pronounced impact on potential exposure to NO2, with an estimated 0.3 μg m−3 (equivalent to 2%) increase in population-weighted annual exposure to NO2 across the whole UK population. Population-weighted exposure to PM2.5 and O3 increased and decreased by 0.3%, respectively, reflecting the different atmospheric processes contributing to the spatio-temporal distributions of these pollutants. We also illustrate how our modelling approach can be utilised to quantify individual-level exposure variations due to modelled time-activity patterns for a number of virtual individuals living and working in different locations in three example cities. Changes in annual-mean estimates of NO2 exposure for these individuals were considerably higher than for the total UK population average when including their workday location. Conducting model-based evaluations as described here may contribute to improving representativeness in studies that use small, portable, automatic sensors to estimate personal exposure to air pollution

Automated pipeline processing X‐ray diffraction data from dynamic compression experiments on the Extreme Conditions Beamline of PETRA III

Presented and discussed here is the implementation of a software solution that provides prompt X‐ray diffraction data analysis during fast dynamic compression experiments conducted within the dynamic diamond anvil cell technique. It includes efficient data collection, streaming of data and metadata to a high‐performance cluster (HPC), fast azimuthal data integration on the cluster, and tools for controlling the data processing steps and visualizing the data using the DIOPTAS software package. This data processing pipeline is invaluable for a great number of studies. The potential of the pipeline is illustrated with two examples of data collected on ammonia–water mixtures and multiphase mineral assemblies under high pressure. The pipeline is designed to be generic in nature and could be readily adapted to provide rapid feedback for many other X‐ray diffraction techniques, e.g. large‐volume press studies, in situ stress/strain studies, phase transformation studies, chemical reactions studied with high‐resolution diffraction etc

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset